2,6-Lutidine → (S)-2-[(1-Benzyl-cyclopentanecarbonyl)-amino]-3-[4-(2,6-dichloro-benzoylamino)-phenyl]-propionic acid

HRID 393424Notes

Reaction equation

HRID 393424 reaction equation
C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33].N1C(C)=CC=CC=1C>ClCCl.CCOCC>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[CH:26][CH:25]=1)=[O:33]

Participants

6

Reactant 3

HCID 79372,6-LutidineHCID 783922,6-Dichlorobenzoyl chlorideHCID 538418674-amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester

Product 1

HCID 10152817(S)-2-[(1-Benzyl-cyclopentanecarbonyl)-amino]-3-[4-(2,6-dichloro-benzoylamino)-phenyl]-propionic acidYield 48.5%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×

Procedure

4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (67 mg, 0.176 mmol) and 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmol) were dissolved in 5 mL of dichloromethane and 2,6-lutidine (50 μL, 0.43 mmol) were added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with 1 N HCl, water, and saturated NaHCO3 and was dried (MgSO4). The crude product was dissolved in 4 mL of methanol and treated with 4 N NaOH (0.1 mL). After 2 hours, the excess base was quenched with 0.1 mL of acetic acid, the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 30 min. The peak eluting at 87% acetonitrile was concentrated and lyophilized to give 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine (46 mg), LR(+)LSIMS: m/z 539 (M+H) (2 Cl)

Workup

  1. washwashed with 1 N HCl, water, and saturated NaHCO3
  2. dry with materialwas dried (MgSO4)
  3. dissolutionThe crude product was dissolved in 4 mL of methanol
  4. additiontreated with 4 N NaOH (0.1 mL)
  5. waitAfter 2 hours
  6. customthe excess base was quenched with 0.1 mL of acetic acid
  7. filtrationthe solution was filtered through a 0.2μ nylon
  8. filtrationfilter
  9. customthe filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column
  10. waitwater containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 30 min
  11. washThe peak eluting at 87% acetonitrile
  12. concentrationwas concentrated

Sources & evidence

ORD record
ord-348c883fde1440e68a1e415e1d7efe8d
Source dataset
uspto-grants-2004_10
Patent number
US06806365B2

Reaction notes

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